Therapeutic beta-lactams

ABSTRACT

Compounds comprising 
                         
or a pharmaceutically acceptable salt or a prodrug thereof, are disclosed, wherein Y is
 
                         
A is —(CH 2 ) 6 —, cis —CH 2 CH═CH—(CH 2 ) 3 —, or —CH 2 C≡C—(CH 2 ) 3 —, wherein 1 or 2 carbon atoms may be substituted with S or O; or A is —(CH 2 ) m —Ar—(CH 2 ) o — wherein Ar is substituted or unsubstituted phenyl or monocyclic heteroaryl, the sum of m and o is from 1 to 4, and wherein one CH 2  may be replaced with S or O; X is S or O; R is a hydrocarbyl or a hydroxyhydrocarbyl moiety having from 1 to 12 carbon atoms; D is independently a moiety comprising from 1 to 6 non-hydrogen atoms; and n is an integer from 0 to 4. Methods, compositions, and medicaments related thereto are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is based, and claims priority under 35 U.S.C. §120 toU.S. Provisional Patent Application No. 61/022,172 filed on Jan. 18,2008, and which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives are currently commerciallyavailable for use in glaucoma management. Eicosanoids and derivativesinclude numerous biologically important compounds such as prostaglandinsand their derivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by αor β [e.g. prostaglandin F_(2α)(PGF_(2β))].

The prostaglandin E analog shown below is disclosed in the followingdocuments, expressly incorporated herein by reference: U.S. Pat. No.5,462,968; 5,698,598; and 6,090,847.

Other EP₂ selective agonists are disclosed in U.S. patent applicationSer. No. 11/009,298, filed Dec. 10, 2004 (now U.S. Pat. No. 7,091,231issued Aug. 15, 2006). Prostaglandin EP₂ selective agonists are believedto have several medical uses. For example, U.S. Pat. No. 6,437,146teaches the use of prostaglandin EP₂ selective agonists “for treating orpreventing inflammation and pain in joint and muscle (e.g., rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis,juvenile arthritis, etc.), inflammatory skin condition (e.g., sunburn,burns, eczema, dermatitis, etc.), inflammatory eye condition (e.g.,conjunctivitis, etc.), lung disorder in which inflammation is involved(e.g., asthma, bronchitis, pigeon fancier's disease, farmer's lung,etc.), condition of the gastrointestinal tract associated withinflammation (e.g., aphthous ulcer, Chrohn's disease, atrophicgastritis, gastritis varialoforme, ulcerative colitis, coeliac disease,regional ileitis, irritable bowel syndrome, etc.), gingivitis,inflammation, pain and tumescence after operation or injury, pyrexia,pain and other conditions associated with inflammation, allergicdisease, systemic lupus crythematosus, scleroderma, polymyositis,tendinitis, bursitis, periarteritis nodose, rheumatic fever, Sjgren'ssyndrome, Behcet disease, thyroiditis, type I diabetes, diabeticcomplication (diabetic microangiopathy, diabetic retinopathy, diabeticneohropathy, etc.), nephrotic syndrome, aplastic anemia, myastheniagravis, uveitis contact dermatitis, psoriasis, Kawasaki disease,sarcoidosis, Hodgkin's disease, Alzheimers disease, kidney dysfunction(nephritis, nephritic syndrome, etc.), liver dysfunction (hepatitis,cirrhosis, etc.), gastrointestinal dysfunction (diarrhea, inflammatorybowel disease, etc.) shock, bone disease characterized by abnormal bonemetabolism such as osteoporosis (especially, postmenopausalosteoporosis), hypercalcemia, hyperparathyroidism, Paget's bonediseases, osteolysis, hypercalcemia of malignancy with or without bonemetastases, rheumatoid arthritis, periodonritis, osteoarthritis,ostealgia, osteopenia, cancer cachexia, calculosis, lithiasis(especially, urolithiasis), solid carcinoma, mesangial proliferativeglomerulonephritis, edema (e.g. cardiac edema, cerebral edema, etc.),hypertension such as malignant hypertension or the like, premenstrualtension, urinary calculus, oliguria such as the one caused by acute orchronic failure, hyperphosphaturia, or the like.”

U.S. Pat. No 6,710,072 teaches the use of EP2 agonists for the treatmentor prevention of “osteoporosis, constipation, renal disorders, sexualdysfunction, baldness, diabetes, cancer and in disorder of immuneregulation . . . various pathophysiological diseases including acutemyocardial infarction, vascular thrombosis, hypertension, pulmonaryhypertension, ischemic heart disease, congestive heart failure, andangina pectoris.”

SUMMARY OF THE INVENTION

Disclosed herein are compounds useful in treating glaucoma, inflammatorybowel disease, the stimulation of hair growth, and the stimulation ofthe conversion of vellus hair to terminal hair. The compounds themselvesare disclosed below.

DESCRIPTION OF THE INVENTION

Disclosed herein are compounds comprising:

-   -   or a pharmaceutically acceptable salt or a prodrug thereof,    -   wherein a dashed line represents the presence or absence of a        covalent bond;    -   Y is

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be substituted with S or O; or A is—(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is substituted or unsubstitutedphenyl or monocyclic heteroaryl, the sum of m and o is from 1 to 4, andwherein one CH₂ may be substituted with S or O;

-   -   X is S or O;    -   R is a hydrocarbyl or a hydroxyhydrocarbyl moiety comprising        from 1 to 12 carbon atoms;    -   D is independently a moiety comprising from 1 to 6 non-hydrogen        atoms; and    -   n is an integer from 0 to 4.

Several of the carbon atoms on these compounds are chiral centers. Whilenot intending to limit the scope of the invention in any way, or bebound in any way by theory, it is believed that many compounds andpharmaceutically active salts or prodrugs thereof having thestereochemistry shown below are particularly useful.

A person of ordinary skill in the art understands the meaning of thestereochemistry associated with the hatched wedge/solid wedge structuralfeatures. For example, an introductory organic chemistry textbook(Francis A. Carey, Organic Chemistry, New York: McGraw-Hill Book Company1987, p. 63) states “a wedge indicates a bond coming from the plane ofthe paper toward the viewer” and the hatched wedge, “represents a bondreceding from the viewer.”

In relation to the identity of A disclosed in the chemical structurespresented herein, in the broadest sense, A is —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms maybe substituted with S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Aris substituted or unsubstituted phenyl or monocyclic heteroaryl, the sumof m and o is from 1 to 3, and wherein one CH₂ may be substituted with Sor O.

In other words, while not intending to be limiting, A may be —(CH₂)₆—,cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is substituted with S or O. For example,while not intending to limit the scope of the invention in any way, Amay be an S substituted moiety such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may be an O substituted moiety such as one of thefollowing or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may have both an O and an S substituted in the chain, suchas one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(o)— whereinAr is substituted or unsubstituted phenyl or monocyclic heteroaryl, thesum of m and o is from 1 to 4, and wherein one CH₂ may be substitutedwith S or O. In other words, while not intending to limit the scope ofthe invention in any way, A comprises from 1 to 4 CH₂ moieties and Ar,e.g. —CH₂—Ar—, —(CH₂)₂—Ar—, —CH₂—ArCH₂—, —CH₂Ar(CH₂)₂—,—(CH₂)₂—Ar(CH₂)₂—, and the like; or

-   A comprises O, from 0 to 3 CH₂ moieties, and Ar, as in for example,    —O—Ar—, Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —O—CH₂—Ar—, —O—CH₂—Ar—(CH₂)₂, and    the like; or-   A comprises S, from 0 to 3 CH₂ moieties, and Ar, as in for example,    —S—Ar—, Ar—CH₂—S—, —S—Ar—(CH₂)₂—, —S—CH₂—Ar—, —S—CH₂—Ar—(CH₂)₂, and    the like.

Ar is substituted or unsubstituted phenyl or substituted orunsubstituted monocyclic heteroaryl. In one embodiment, Ar issubstituted or unsubstituted phenyl, thienyl, furyl, or pyridinyl. Inanother embodiment Ar is phenyl (Ph). In another embodiment A is—(CH₂)₂-Ph. While not intending to limit scope of the invention in anyway, substituents may have 4 or less heavy atoms, or in other words, nonhydrogen atoms. Any number of hydrogen atoms required for a particularsubstituent will also be included. Thus, the substituent may be C₄ orlower hydrocarbyl, including C₄ or lower alkyl, including methyl, ethyl,propyl isomers including isopropyl, butyl isomers including t-butyl, andalkenyl, alkynyl, and the like; C₃ or lower hydrocarbyloxy includingalkoxy such as methoxy, ethoxy, etc.; CF₃; halo, such as F, Cl, or Br;hydroxyl; NH₂ and alkylamine functional groups up to C₃; other N or Scontaining substituents; and the like.

In one embodiment A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is phenyl,the sum of m and o is from 1 to 3, and wherein one CH₂ may besubstituted with S or O.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂—Ar—OCH₂— and Ar is phenyl. In another embodiment, Ar is attached atthe 1 and 3 positions, such as when A has the structure shown below.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with Sor O; or A is —(CH₂)₂-Ph- wherein one CH₂ may be substituted with S orO.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with Sor O; or A is —(CH₂)₂-Ph-.

D is a moiety comprising from 1 to 6 non-hydrogen atoms, in other words,there are from 1 to 6 atoms which are not hydrogen, and any number ofhydrogen atoms required to form the complete substituent. For example, amethyl substituent has 1 carbon atom and 3 hydrogen atoms. Other examplesubstituents include other hydrocarbyl moieties comprising from 1 to 6carbon atoms including alkyl such as ethyl, propyl, isopropyl, butyl andisomers thereof, pentyl and isomers thereof, hexyl and isomers thereof;cyclic and unsaturated hydrocarbyls having 1 to 6 carbon atoms; CO₂H andsalts thereof; alkoxy up to C₅ such as methoxy, ethoxy, propoxy,isopropoxy, a butoxy isomer, or a pentoxy isomer; carboxylic acidesters; CN; NO₂; CF₃; F; Cl; Br; I; sulfonyl esters; SO₃H and saltsthereof; and the like. D may be in any reasonable position on the phenylring.

In certain compounds, n is 0. In other compounds n is 1, in othercompounds n is 2, and in other compounds n is 3.

A hydrocarbyl moiety refers to a moiety consisting of only carbon andhydrogen. While not intending to limit the scope of the invention in anyway, examples of different types of hydrocarbyl moiety are as follows.

Hydrocarbyl is a moiety consisting of only carbon and hydrogen, andincludes, but is not limited to alkyl, alkenyl, alkynyl, and the like,and in some cases aryl, and combinations thereof.

Alkyl is hydrocarbyl having no double or triple bonds including:

linear alkyl such as methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl,and the like;

branched alkyl such as isopropyl, branched butyl isomers (i.e.sec-butyl, tert-butyl, etc), branched pentyl isomers (i.e. isopentyl,etc), branched hexyl isomers, and higher branched alkyl fragments;

cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc.; and alkyl fragments consisting of both cyclic andnoncyclic components, whether linear or branched, which may be attachedto the remainder of the molecule at any available position includingterminal, internal, or ring carbon atoms.

Alkenyl is hydrocarbyl having one or more double bonds including linearalkenyl, branched alkenyl, cyclic alkenyl, and combinations thereof inanalogy to alkyl.

Alkynyl is hydrocarbyl having one or more triple bonds including linearalkynyl, branched alkynyl, cyclic alkynyl and combinations thereof inanalogy to alkyl.

Aryl is an unsubstituted or substituted aromatic ring or ring systemsuch as phenyl, naphthyl, biphenyl, and the like. Aryl may or may not behydrocarbyl, depending upon whether it has substituents withheteroatoms.

Arylalkyl is alkyl which is substituted with aryl. In other words alkylconnects aryl to the remaining part of the molecule. Examples are—CH₂-Phenyl, —CH₂—CH₂-Phenyl, and the like. Arylalkyl may or may not behydrocarbyl, depending upon whether it has substituents withheteroatoms.

Another type of hydrocarbyl is alk(poly)enyl, which is similar toalkenyl, except that more than one double bond is present.

Another type of hydrocarbyl is alkynyl or an alk(poly)ynyl, which issimilar to alkenyl or alk(poly)ynyl except that one or more triple bondsare present.

A hydrocarbyl moiety comprising a cyclic structure comprises acycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl(poly)enyl,cycloalkyl(poly)ynyl, aryl, and the like; and may consist of only thering or may be a combination of the ring and one or more of the linear,branched, or cyclic hydrocarbyl fragments; or may be a fused polycyclicstructure. Combinations of the above are also possible.

Additionally, combinations of any of the above in any manner imaginableto those of ordinary skill in the art are also hydrocarbyl.

For the compounds disclosed herein, hydrocarbyl having no ring has 12 orfewer carbon atoms, and hydrocarbyl having one or more rings has 18 orfewer carbon atoms.

A hydroxyhydrocarbyl moiety consists of a combination of a hydrocarbylmoiety and a hydroxyl group. In other words, a hydrogen atom of thehydrocarbyl moiety is substituted with a hydroxyl group. Thehydroxyhydrocarbyl moiety attaches to the remainder of the molecule at acarbon atom.

Thus, while not intending to limit the scope of the invention in anyway, as R is a hydrocarbyl or a hydroxyhydrocarbyl moiety comprisingfrom 1 to 12 atoms, embodiments having R as any of the hydrocarbyl orhydroxycarbyl moieties listed above are specifically contemplatedherein. R may also be a different moiety which may be consideredhydrocarbyl or hydroxyhydrocarbyl according to the description givenherein.

In other embodiments, R is not methyl, ethyl.

In other embodiments R comprises from 4 to 12 carbon atoms.

In certain compounds, R is a hydroxyhydrocarbyl having the hydroxylgroup attached to the carbon atom which is also attached to theremainder of the molecule. In other words the hydroxyl group and theremainder of the molecule are on geminal positions on the hydrocarbylmoiety. This type of hydroxyhydrocarbyl moiety is referred to as a1-hydroxyhydrocarbyl moiety herein. Non-linear hydroxyhydrocarbyl ishydroxyhydrocarbyl wherein the hydrocarbyl portion is not linear, i.e.it has branching and/or a ring.

In other compounds R is hydroxyhydrocarbyl where there are two carbonatoms connecting the hydroxyl group to the remaining part of themolecule. These particular hydroxyhydrocarbyl are called2-hydroxyhydrocarbyl herein. For example, —CH₂CH₂OH and —C(CH₃)₂CH₂OHare 2-hydroxyhydrocarbyl. While not intending to limit the scope of theinvention in any way, an example of a structure where R is 2-hydrocarbylis shown below.

As with all other structures shown herein, pharmaceutically acceptablesalts and prodrugs of compounds represent by these structures are alsocontemplated.

In one embodiment related to the above structure, R³, R⁴, and R⁵ areindependently H or C₁₋₆ alkyl. As the dashed line indicates the presenceor absence of a bond, R⁴ and R⁵ may be two separate moieties. Forexample, while not intending to be limiting, R⁴ and R⁵ may be methyl,and no bond would be present where indicated by the dashed line.Alternatively, while not intending to limit the scope of the inventionin any way, R⁴ and R⁵ may form a ring. In other words, a compound suchas the one shown below is possible, wherein x is from 1 to 6.

Pharmaceutically acceptable salts and prodrugs of compounds represent bythese structures are also contemplated.

In certain compounds, R comprises from 6 to 9 carbon atoms and a cyclicstructure. In other compounds, R comprises from 1 to 5 carbon atoms. Incertain compounds R is hydroxyalkyl having from 1 to 5 carbon atoms. Inother compounds R is a 1-hydroxyhydrocarbyl moiety comprising from 6 to9 carbon atoms and a cyclic structure. In other compounds R is a1-hydroxyhydrocarbyl moiety comprising from 6 to 9 carbon atoms and acyclic structure comprising from 4-7 carbon atoms. In other words, thecyclic structure part of R is a cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl fragment. The cyclic structure part of R may also be acycloalkenyl or cycloalkynyl fragment such as cyclopentene orcyclohexene. In other compounds R is a hydrocarbyl moiety comprisingfrom 1 to 5 carbon atoms. In other words, R is methyl, ethyl, propyl,isopropyl, a butyl isomer such as t-butyl, or a pentyl isomer. Incertain compounds R is t-butyl.

Certain R groups are specifically contemplated herein. These are shownbelow, where PR represents the remaining part of the molecule.

As there is a dashed line between R and the phenyl ring, cyclicstructures having two carbon atoms of the phenyl ring are possible.While not intending to limit the scope of the invention in any way,compounds such as those represented by the structure below are thereforepossible.

Pharmaceutically acceptable salts and prodrugs thereof are alsocontemplated.

Other useful compounds comprise

or a pharmaceutically acceptable salt, or a prodrug thereof.

Certain useful compounds comprise

or a pharmaceutically acceptable salt, or a prodrug thereof.

Other useful examples of compounds comprise

or a pharmaceutically acceptable salt, or a prodrug thereof.

Other compounds comprise

or a pharmaceutically acceptable salt, or a prodrug thereof.

Other embodiments comprise

or a pharmaceutically acceptable salt, or a prodrug thereof,

-   -   wherein a dashed line indicates the presence or absence of a        bond.

Other compounds comprise

or a pharmaceutically acceptable salt or a prodrug thereof.

Other compounds comprise

or a pharmaceutically acceptable salt, or a prodrug thereof,wherein R⁶ is cycloalkyl comprising from 3 to 10 carbon atoms.

Other compounds comprise

or a pharmaceutically acceptable salt, or a prodrug thereof,wherein R⁶ is branched alkyl comprising from 3 to 10 carbon atoms.

Other compounds comprise

or a pharmaceutically acceptable salt, or a prodrug thereof.

Other embodiments comprise

or a pharmaceutically acceptable salt, or a prodrug thereofwherein m is an integer having a value of from 0 to 3.

Those of ordinary skill in the art understand that any value whichrefers to the number of atoms, moieties, etc., on a small molecule willbe an integer, i.e. 0, 1, 2, 3, etc.

Other compounds comprise

or a pharmaceutically acceptable salt, or a prodrug thereof.

Other compounds comprise

or a pharmaceutically acceptable salt, or a prodrug thereof.

Other useful compounds comprise

or a pharmaceutically acceptable salt, or a prodrug thereof.

Other compounds comprise

or a pharmaceutically acceptable salt or a prodrug thereof.

Other useful embodiments comprise

or a pharmaceutically acceptable salt or a prodrug thereof.

Other compounds comprise

or a pharmaceutically acceptable salt or a prodrug thereof.

Other compounds comprise

or a pharmaceutically acceptable salt or a prodrug thereof.

The following are examples of useful compounds

Pharmaceutically acceptable salts or prodrugs of these compounds arealso useful.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into a salt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions, lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted.

The compounds disclosed herein are useful for the prevention ortreatment of glaucoma or ocular hypertension in mammals, or for themanufacture of a medicament for the treatment of glaucoma or ocularhypertension.

The compounds disclosed herein may also be useful for the stimulation ofhair growth or stimulate conversion of vellus hair to terminal hair inmammals, or for the manufacture of a medicament for the stimulation ofhair growth or stimulate conversion of vellus hair to terminal hair.

The compounds disclosed herein will be selective EP₂ agonists.Therefore, they are also useful for the treatment of those diseasesdisclosed in the art as being amenable to treatment by prostaglandin EP₂agonist, such as the ones listed previously.

Ophthalmic Applications

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distcaratemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administeredis, of course, dependent on the therapeutic effect or effects desired,on the specific mammal being treated, on the severity and nature of themammal's condition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds ispreferably in the range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10   pHadjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,co-solvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

Applications for Stimulating Hair Growth

In one embodiment, the compounds disclosed herein can be useful in thetreatment of baldness and/or hair loss. Alopecia (baldness) is adeficiency of either normal or abnormal hair, and is primarily acosmetic problem in humans. It is a deficiency of terminal hair, thebroad diameter, colored hair that is readily seen. However, in the socalled bald person, although there is a noticeable absence of terminalhair, the skin does contain vellus hair, which is a fine colorless hairwhich may require microscopic examination to determine its presence.This vellus hair is a precursor to terminal hair.

The compounds described herein can be used to stimulate, such as theconversion of vellus hair to growth as terminal hair, as well asincreasing the rate of growth of terminal hair. The utility of thecompounds described herein for the simulation of hair growth wasdiscovered as follows.

In the course of treating patients having glaucoma, treatment may onlybe appropriate in one eye. Within the course of daily practice, it wasdiscovered that a patient who had been treated with bimatoprost, aprostaglandin analogue, developed lashed that were longer, thicker, andfuller in the treated eye than in the non-treated eye. On examination,the difference was found to be very striking. The lashes were longer andhad a fuller, denser appearance in the treated eye. The lash appearanceon the lids of the treated eyes would have appeared quite attractive ifit represented a bilateral phenomenon. As a result of its asymmetricnature, the long lashes on one side could be construed as disturbingfrom a cosmetic standpoint. A systemic examination was preformed as aresult of the asymmetric phenomenon. It soon became apparent that thisaltered appearance was not an isolated finding. Comparison of the lidsof patients who were taking bimatoprost in only one eye revealed subtlechanges in the lashed and adjacent hairs of the bimatoprost-treated sidein several patients. Definite differences could be identified to varyingdegrees in the lashes and adjacent hairs of all patients who were takingthe drug on a unilateral basis for longer than 6 months.

The changes in the lashes were apparent on gross inspection in severalpatients once attention was focused on the issue. In those with lightcolored hair and lashes, the differences were only seen easily with theaid of the high magnification and lighting capabilities of the slit lampbiomicroscope. In the course of glaucoma follow-up examination,attention is generally immediately focused on the eye itself. As aresult of the high power magnification needed only one eye is seen at atime and the eye is seen at a high enough power that the lashes are notin focus. At these higher powers, any lash asymmetry between the twoeyes is not likely to be noticed except by careful systematic comparisonof the lashes and adjacent hairs of the eyelids of the two eyes.

Observed parameters leading to the conclusion that more robust hairgrowth occurred in the treatment area following administration of theprostaglandin analogue were multiple. They included increased length oflashed, increased number of lashes along the normal lash line, increasedthickness and luster of lashes, increased auxiliary lash-like terminalhair in transitional areas adjacent to areas of normal lash growth,increased auxiliary lash-like terminal hairs at the medial and lateralcanthal area, increased pigmentation of the lashes, increased numbers,increased length, as well as increased luster, and thickness of finehair on the skin of the adjacent lid, and finally, increasedperpendicular angulation of lashes and lash-like terminal hairs. Theconclusion that hair growth is stimulated by prostaglandin analoguessuch as bimatoprost is thus supported not by evidence of a difference ina single parameter, but is based on multiple parameters of hairappearance in treated versus control areas in many subjects.

The compounds described herein are prostaglandin analogues and thereforehave similar activities as bimatoprost, contain structural similarities,and therefore are expected to stimulate hair growth and stimulation ofthe conversion of vellus hair to terminal hair. In one embodiment, thecompounds described herein and their prodrugs can be used for thestimulation of hair growth. As used herein, hair growth includes hairassociated with the scalp, eyebrows, eyelids, beard, and other areas ofthe skin of animals.

In one embodiment, the compound is mixed with a dermatologicallycompatible vehicle or carrier. The vehicle, which may be employed forpreparing compositions as described herein, may comprise, for example,aqueous solutions such as e.g., physiological salines, oil solutions, orointments. The vehicle furthermore may contain dermatologicallycompatible preservatives such as e.g., benzalkonium chloride,surfactants like e.g., polysorbate 80, liposomes or polymers, forexample, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone andhyaluronic acid; these may be used for increasing the viscosity.Furthermore, it is also possible to use soluble or insoluble druginserts when the drug is to be administered.

In one embodiment, dermatological compositions can be formulated fortopical treatment for the stimulation of hair growth which comprises aneffective hair growth simulating amount of one or more compounds asdefined above and a dermatologically compatible carrier. Effectiveamounts of the active compounds may be determined by one of ordinaryskill in the art, but will vary depending on the compound employed,frequency of application and desired result. The compound will generallyrange from about 0.0000001 to about 50% by weight of the dermatologicalcomposition. Preferably, the compound will range from about 0.001 toabout 50% by weight of total dermatological composition, more preferablyfrom about 0.1 to about 30% by weight of the composition.

In one embodiment, the application of the present compounds forstimulation of hair growth finds applications in mammalian species,including both humans and animals. In humans, the compounds describedherein can be applied for example, to the scalp, face beard, head, pubicarea, upper lip, eyebrows, and eyelids. In animal raised for theirpelts, e.g., mink, the compounds described herein can be applied overthe entire surface of the body to improve the overall pelt forcommercial reasons. The process can also be used for cosmetic reasons inanimals, e.g., applied to the skin of dogs and cats having bald patchesdue to mange or other diseases causing a degree of alopecia.

The pharmaceutical compositions contemplated for the stimulation of hairgrowth include pharmaceutical compositions suited for topical and localaction. The term “topical” as employed herein relates to the use of acompound, as described herein, incorporated in a suitable pharmaceuticalcarrier, and applied at the site of thinning hair or baldness forexertion of local action. Accordingly, such topical compositions includethose pharmaceutical forms in which the compound is applied externallyby direct contact with the skin to be treated. Conventionalpharmaceutical forms for this purpose include ointments, liniments,creams, shampoos, lotions, pastes, jellies, sprays, aerosols, and thelike, and may be applied in patches or impregnated dressings dependingon the part of the body to be treated. The term “ointment” embracesformulations (including creams) having oleaginous, water-soluble andemulsion-type bases, e.g., petrolatum, lanolin, polyethylene glycols, aswell as mixtures of these.

Typically, the compounds can be applied repeatedly for the sustainedperiod of time topically on the part of the body to be treated, forexample, the eyelids, eyebrows, skin or scalp. The preferred dosageregimen will generally involve regular, such as daily, administrationfor a period of treatment of at least one month, more preferably atleast three months, and most preferably, at least six months.

For topical use on the eyelids or eyebrows, the active compounds can beformulated in aqueous solutions, creams, ointments, or oils exhibitingphysologicla acceptable osmolarity by addition of pharmaceuticallyacceptable buffers and salts. such formulations may or may not,depending on the dispenser, contain preservatives such as benzalkoniumchloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acids andphenylmercuric salts such as nitrate, chloride, acetate, and borate, orantioxidants, as well as additives like EDTA, sorbitol, boric acid andthe like as additives. Furthermore, particularly aqueous solutions maycontain viscosity increasing agents such as polysaccharides, e.g.,methylcellulose, mucopolysaccharides, e.g., hyaluronic acid andchondroitin sulfate, or poly alcohol, e.g., polyvinylalcohol. Variousslow releasing gels and matricies may also be employed as well assoluble and insoluble ocular inserts, for instance, based on substancesforming in situ gels. Depending on the actual formation and compound tobe used, various amounts of the drug and different dose regimens may beemployed. Typically, the daily amount of compound for treatment of theeyelid may be about 0.1 ng to about 100 mg per eyelid.

For topical use on the skin and scalp, the compound can beadvantageously formulated using ointments, creams, liniments or patchesas a carrier of the active ingredient. Also, these formulations may ormay not contain preservatives, depending on the dispenser and nature ofuse. Such preservatives include those mentioned above, and methyl-,propyl-, or butyl-parahydroxybenzoic acid, betain, chlorhexidine,benzalkonium chloride, and the like. Various matricies for the slowrelease delivery may also be used. Typically, the dose to be applied onthe scalp is in the range of about 0.1 ng to about 100 mg per day, morepreferably about 1 ng to about 10 mg per day, and most preferably about10 ng to about 1 mg per day depending on the compound and theformulation. To achieve the daily amount of medication depending on theformulation, the compound may be administered once or several timesdaily with or without antioxidants.

Specifically Contemplated Embodiments

In addition to any other embodiments disclosed herein, the followingembodiments are specifically contemplated.

Compound Embodiment

A compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof,wherein a dashed line represents the presence or absence of a covalentbond;

-   -   Y is

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be substituted with S or O; or A is—(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is substituted or unsubstitutedphenyl or monocyclic heteroaryl, the sum of m and o is from 1 to 4, andwherein one CH₂ may be substituted with S or O;

-   -   X is S or O;    -   R is a hydrocarbyl or a hydroxyhydrocarbyl moiety comprising        from 1 to 12 carbon atoms;    -   D is independently a moiety comprising from 1 to 6 non-hydrogen        atoms; and    -   n is an integer from 0 to 4.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein Y, A, and R are as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof;

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein A and Y are as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein Y and R are as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein Y is as described above; and

-   -   R is alkyl having from 3 to 6 carbon atoms.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof,wherein Y is as described above; and

-   -   R⁶ is cycloalkyl comprising from 3 to 10 carbon atoms.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein Y is as described above; and

-   -   m is an integer having a value of from 0 to 3.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof;wherein R³, R⁴, and R⁵ are independently H or C₁₋₆ alkyl.

In another embodiment R⁴ and R⁵ are methyl in the structure above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

Other compounds comprise

or a pharmaceutically acceptable salt or a prodrug thereof.

Other compounds comprise

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment n is 0 in any structure shown above.

In another embodiment R comprises from 6 to 9 carbon atoms and a cyclicstructure in any structure shown above.

In another embodiment R is a 1-hydroxyhydrocarbyl moiety in anystructure shown above.

In another embodiment R comprises from 1 to 5 carbon atoms in anystructure shown above.

In another embodiment R consists of t-butyl in any structure shownabove.

In another embodiment R is 1-hydroxyalkyl in any structure shown above.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃— in any structure shown above.

In another embodiment A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar isphenyl, the sum of m and o is from 1 to 4, and wherein one CH₂ may besubstituted with S or O in any structure shown above.

In another embodiment A is —CH₂—Ar—O—CH₂— in any structure shown above.

In another embodiment R is 2-hydroxyhydrocarbyl in any structure shownabove.

Method of Treating Embodiments

Glaucoma or Ocular Hypertension

For each embodiment drawn to a compound, a corresponding embodiment iscontemplated drawn to administering the compound to a mammal for thetreatment of glaucoma or ocular hypertension.

Inflammatory Bowel Disease

For each embodiment drawn to a compound, a corresponding embodiment iscontemplated drawn to administering the compound to a mammal for thetreatment of inflammatory bowel disease.

In another embodiment said inflammatory bowel disease is colitis.

In another embodiment said inflammatory bowel disease is Crohn'sdisease.

Baldness or Hair Loss

For each embodiment drawn to a compound, a corresponding embodiment iscontemplated drawn to administering the compound to a mammal for thestimulation of hair growth or the stimulation of the conversion ofvellus hair to terminal hair.

Method of Manufacturing Medicaments Embodiments

Glaucoma or Ocular Hypertension

For each embodiment drawn a compound, a corresponding embodiment iscontemplated drawn to use of the compound in the manufacture of amedicament for the treatment of glaucoma.

Inflammatory Bowel Disease

One embodiment is a use of a compound in the manufacture of a medicamentfor the treatment of inflammatory bowel disease.

Baldness or Hair Loss

One embodiment is a use of a compound in the manufacture of a medicamentfor the stimulation of hair growth or the stimulation of the conversionof vellus hair to terminal hair.

In one embodiment, said compound can be used in the manufacture of amedicament for the treatment of glaucoma, treatment of inflammatorybowel disease, and/or stimulation of hair growth or the stimulation ofthe conversion of vellus hair to terminal hair, said compoundcomprising:

or a pharmaceutically acceptable salt or a prodrug thereof,wherein a dashed line represents the presence or absence of a covalentbond;

-   -   Y is

-   -   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—,        wherein 1 or 2 carbon atoms may be substituted with S or O; or A        is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is substituted or        unsubstituted phenyl or monocyclic heteroaryl, the sum of m and        o is from 1 to 4, and wherein one CH₂ may be substituted with S        or O;    -   X is S or O;    -   R is a hydrocarbyl or a hydroxyhydrocarbyl moiety comprising        from 1 to 12 carbon atoms;    -   D is independently a moiety comprising from 1 to 6 non-hydrogen        atoms; and    -   n is an integer from 0 to 4.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein Y, A, and R are as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein A and Y are as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein Y and R are as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein Y is as described above; and

-   -   R is alkyl having from 3 to 6 carbon atoms.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof,wherein Y is as described above; and

-   -   R⁶ is cycloalkyl comprising from 3 to 10 carbon atoms.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein Y is as described above; and

-   -   m is an integer having a value of from 0 to 3.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof;wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof,wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof,wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof,wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt, or a prodrug thereof,wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof;wherein R³, R⁴, and R⁵ are independently H or C₁₋₆ alkyl.

In another embodiment R⁴and R⁵ are methyl in the structure above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof,wherein Y is as described above.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment n is 0 in any structure shown above.

In another embodiment R comprises from 6 to 9 carbon atoms and a cyclicstructure in any structure shown above.

In another embodiment R is a 1-hydroxyhydrocarbyl moiety in anystructure shown above.

In another embodiment R comprises from 1 to 5 carbon atoms in anystructure shown above.

In another embodiment R consists of t-butyl in any structure shownabove.

In another embodiment R is 1-hydroxyalkyl in any structure shown above.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃— in any structure shown above.

In another embodiment A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar isphenyl, the sum of m and o is from 1 to 4, and wherein one CH₂ may besubstituted with S or O in any structure shown above.

In another embodiment A is —CH₂—Ar—O—CH₂— in any structure shown above.

In another embodiment R is 2-hydroxyhydrocarbyl in any structure shownabove.

In another embodiment said inflammatory bowel disease is colitis.

In another embodiment said inflammatory bowel disease is Crohn'sdisease.

Composition Embodiments

For each embodiment drawn to a compound, there is a correspondingembodiment drawn to a composition comprising said compound, wherein saidcomposition is a liquid which is ophthalmically acceptable.

Synthetic Procedures

While there are many ways the compound disclosed herein may be prepared,in one method (Scheme 1) a vinyl benzaldehyde, commercially availablefrom Aldrich, is treated with any appropriate alkyl metalate such as alithiate, to form an alkylated alcohol. The resultant alcohols couldthen be protected and the resultant styrene derivatives could be treatedas decribed by Forró and F{acute over (ú)}löp (Tetrahedron: Assymmetry12 (2001) 2351-2358) to form enantiomerically pure β-lactams. Theα-chain may be then added by adapting procedures known in the art, suchas those described in U.S. Patent Application Publication No.20030207925, U.S. Patent Application Publication No. 20030120079, andU.S. Pat. No. 6,747,054.

Alternatively (Scheme 2), a vinyl-substituted benzyl alcohol could beused as the substrate in the β-lactam forming reaction. Subsequent toβ-lactam formation and introduction of the alpha chain (by theprocedures discussed above), the benzylic alcohol is deprotected andoxidized to an aldehyde, which may be reacted by a nucleophile such as aGrignard reagent to complete the ω-chain and form the desired compound.See U.S. Pat. No. 7,091,231, filed Dec. 10, 2004, for an example of thismethod.

Another method of synthesis involves that of Scheme 3. Synthesis ofCompound 1 below involves procedures outlined above. Introduction of thealpha chain (by the procedures discussed above) involves addition ofmethyl 5-(3-bromopropyl)thiophene-2-carboxylate (synthesis described inWO94/13295). The methyl ester is then converted to a carboxylic acid byester hydrolysis, forming Compound 1.

Triethylamine (15 μL) and ethyl chloroformate (15 μL) are addedsequentially to a solution of compound 1 (10.5 mg) in CH₂Cl₂ (0.2 mL) atroom temperature. After 2.5 h, triethylamine (15 μL) and ethylene glycol(200 μL) are added. After stirring overnight at room temperature, thereaction mixture is partitioned between H₂O (5 mL) and CH₂Cl₂ (5 mL).The phases are separated and the aqueous phase is extracted with CH₂Cl₂(2×5 mL). The combined organic phase is washed with 1 N HCl (5 mL) thendried (MgSO₄), filtered and concentrated in vacuo. Purification of theresidue by flash column chromatography on silica gel (10% CH₃OH/CH₂Cl₂)affords 2.5 mg (22%) of the title compound 2.

Compound 3

Triethylamine (6.5 μL) and ethyl chloroformate (7 μL) are addedsequentially to a solution of compound 1 (20 mg) in CH₂Cl₂ (0.47 mL) atroom temperature. After 2.5 h, triethylamine (6.5 μL) and4-(2-hydroxyethyl)-morphine (58 μL) are added. After stirring overnightat room temperature, the reaction mixture is partitioned between H₂O (5mL) and CH₂Cl₂ (5 mL). The phases are separated and the aqueous phase isextracted with CH₂Cl₂ (2×5 mL). The combined organic phase is washedwith 1 N HCl (5 mL) then dried (MgSO₄), filtered and concentrated invacuo. Purification of the residue by flash column chromatography onsilica gel (10% CH₃OH/CH₂Cl₂) affords 5.1 mg (20%) of the title compound3.

In Vivo Examples

Title compounds 2 and 3 from above are tested in vivo to measure itsability to reduce intraocular pressure. Compound 2 is tested innormotensive dogs. The intraocular pressure (IOP) decreases frombaseline. This compound is also tested in laser-induced hypertensivemonkeys, the IOP decreases from baseline.

Compound 3 is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

Biological Activity

The activity of compounds disclosed herein is tested according to thefollowing procedures.

Radioligand Binding

Cells Stably Expressing EP₁, EP₂, EP₄ and FP Receptors

HEK-293 cells stably expressing the human or feline FP receptor, or EP₁,EP₂, or EP₄ receptors are washed with TME buffer, scraped from thebottom of the flasks, and homogenized for 30 sec using a Brinkman PT10/35 polytron. TME buffer is added to achieve a final 40 ml volume inthe centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mMMgCl₂, 2M EDTA; 10N HCl is added to achieve a pH of 7.4).

The cell homogenate is centrifuged at 19000 r.p.m. for 20 min at 4° C.using a Beckman Ti-60 rotor. The resultant pellet is resuspended in TMEbuffer to give a final 1 mg/ml protein concentration, as determined byBiorad assay. Radioligand binding competition assays vs. [³H—]17-phenylPGF_(2α) (5 nM) are performed in a 100 μl volume for 60 min. Bindingreactions are started by adding plasma membrane fraction. The reactionis terminated by the addition of 4 ml ice-cold TRIS-HCl buffer and rapidfiltration through glass fiber GF/B filters using a Brandel cellharvester. The filters are washed 3 times with ice-cold buffer and ovendried for one hour. Non-specific binding is determined with 10 uMunlabeled 17-phenyl PGF_(2α).

[³H—] PGE₂ (5 nM; specific activity 180 Ci mmol) is used as theradioligand for EP receptors. Binding studies employing EP₁, EP₂, EP₃,EP₄ are performed in duplicate in at least three separate experiments. A200 μl assay volume is used. Incubations are for 60 min at 25° C. andare terminated by the addition of 4 ml of ice-cold 50 mM TRIS-HCl,followed by rapid filtration through Whatman GF/B filters and threeadditional 4 ml washes in a cell harvester (Brandel). Non-specificbinding is determined with 10⁻⁵M of unlabeled PGE₂.

Methods for FLIPR™ Studies

(a) Cell Culture

HEK-293(EBNA) cells, stably expressing one type or subtype ofrecombinant human prostaglandin receptors (prostaglandin receptorsexpressed: hDP/Gqs5; hEP₁; hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5; hFP;hIP; hTP), are cultured in 100 mm culture dishes in high-glucose DMEMmedium containing 10% fetal bovine serum, 2 mM I-glutamine, 250 μg/mlgeneticin (G418) and 200 μg/ml hygromycin B as selection markers, and100 units/ml penicillin G, 100 □g/ml streptomycin and 0.25 μg/mlamphotericin B.

(b) Calcium Signal Studies on the FLIPR™

Cells are seeded at a density of 5×10⁴ cells per well in Biocoat®Poly-D-lysine-coated black-wall, clear-bottom 96-well plates(Becton-Dickinson) and allowed to attach overnight in an incubator at37° C. Cells are then washed two times with HBSS-HEPES buffer (HanksBalanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES,pH 7.4) using a Denley Cellwash plate washer (Labsystems). After 45minutes of dye-loading in the dark, using the calcium-sensitive dyeFluo-4 AM at a final concentration of 2 μM, plates are washed four timeswith HBSS-HEPES buffer to remove excess dye leaving 100 μL in each well.Plates are re-equilibrated to 37° C. for a few minutes.

Cells are excited with an Argon laser at 488 nm, and emission ismeasured through a 510-570 nm bandwidth emission filter (FLIPR™,Molecular Devices, Sunnyvale, Calif.). Drug solution is added in a 50 μlvolume to each well to give the desired final concentration. The peakincrease in fluorescence intensity is recorded for each well. On eachplate, four wells each serve as negative (HBSS-HEPES buffer) andpositive controls (standard agonists: BW245C (hDP); PGE₂ (hEP₁;hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5); PGF_(2α) (hFP); carbacyclin (hIP);U-46619 (hTP), depending on receptor). The peak fluorescence change ineach drug-containing well is then expressed relative to the controls.

Compounds are tested in a high-throughput (HTS) orconcentration-response (CoRe) format. In the HTS format, forty-fourcompounds per plate are examined in duplicates at a concentration of10⁻⁵ M. To generate concentration-response curves, four compounds perplate are tested in duplicates in a concentration range between 10⁻⁵ and10⁻¹¹ M. The duplicate values are averaged. In either, HTS or CoReformat each compound is tested on at least 3 separate plates using cellsfrom different passages to give an n≧3.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

1. A compound of the formula

or a pharmaceutically acceptable salt or a prodrug thereof, wherein adashed line represents the presence or absence of a covalent bond; Y is

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be substituted with S or O; or A is—(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is substituted or unsubstitutedphenyl or monocyclic heteroaryl, the sum of m and o is from 1 to 4, andwherein one CH₂ may be replaced with S or O; X is S or O; R is ahydrocarbyl or a hydroxyhydrocarbyl moiety having from 1 to 12 carbonatoms; D is independently a moiety comprising from 1 to 6 non-hydrogenatoms; and n is an integer from 0 to
 4. 2. The compound of claim 1,wherein n is
 0. 3. The compound of claim 1, wherein R comprises from 6to 9 carbon atoms.
 4. The compound of claim 3 of the formula

or a pharmaceutically acceptable salt, or a prodrug thereof.
 5. Thecompound of claim 3 of the formula

or a pharmaceutically acceptable salt, or a prodrug thereof.
 6. Thecompound of claim 1 of the formula

or a pharmaceutically acceptable salt, or a prodrug thereof.
 7. Thecompound of claim 1 of the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 8. Thecompound of claim 1 wherein A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—.
 9. The compound of claim 2 of the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 10. Thecompound of claim 2 of the formula

or a pharmaceutically acceptable salt or a prodrug thereof; wherein R³,R⁴, and R⁵ are independently H or C₁₋₆ alkyl and the dashed lineindicates the presence or absence of a bond, R⁴ and R⁵ may be twoseparate moieties.
 11. The compound of claim 10 wherein R⁴ and R⁵ aremethyl.
 12. The compound of claim 11 of the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 13. Thecompound of claim 2, wherein A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar isphenyl, the sum of m and o is from 1 to 4, and wherein one CH₂ may bereplaced with S or O.
 14. The compound of claim 1 of the formula

or a pharmaceutical acceptable salt or a prodrug thereof.
 15. A methodof treatment of glaucoma or ocular hypertension comprising administeringa compound according to claim 1 to a mammal and treating glaucoma orocular hypertension.
 16. A composition comprising a compound accordingto claim 1, wherein said composition is a liquid which is ophthalmicallyacceptable and a pharmaceutically suitable carrier.
 17. A method oftreatment of baldness comprising administering a compound according toclaim 1 to a mammal and treating baldness.
 18. A method of treatment ofhair loss comprising administering a compound according to claim 1 to amammal and treating hair loss.
 19. The compound of claim 1 of theformula:

or a pharmaceutically acceptable salt or a prodrug thereof.
 20. Thecompound of claim 1 of the formula:

or a pharmaceutically acceptable salt or a prodrug thereof.